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Pharyngeal Swallowing: Defining Pharyngeal and Upper Esophageal Sphincter Relationships in Human Neonates
Pharyngeal Swallowing: Defining Pharyngeal and Upper Esophageal Sphincter Relationships in Human Neonates SUDARSHAN RAO JADCHERLA, MD, FRCPI, DCH, ALANKAR GUPTA, MD, MS, ERIN STONER, RN, BSN, SOLEDAD FERNANDEZ, PHD, AND REZA SHAKER, MD
Objective To test the hypothesis that the sensorimotor characteristics of the reflexes evoked on stimulation with air and water infusions differ by studying the effect of pharyngeal stimulation on pharyngeal– upper esophageal sphincter (UES) interactions in healthy neonates. Study design Pharyngo-UES-esophageal manometry was recorded in 10 neonates at 39 ⴞ 4 weeks postmenstrual age. Pharyngeal infusions (n ⴝ 155) of air (0.1 to 2.0 mL) and sterile water (0.1 to 0.5 mL) were given. Two types of reflexes were recognized: pharyngeal reflexive swallowing (PRS) and pharyngo-UES-contractile reflex (PUCR). Frequency occurrence, distribution of reflexes, threshold volume, response time, and stimulus–response relationship were evaluated. Results The reflex response rates were 30% for air and 76% for water (P < .001). PRS was more frequent than PUCR with air and water (P < .05), even though the stimulation thresholds and response latencies were similar. Graded volumes of water but not air resulted in an increased frequency of PRS (P < .01). Conclusions PRS is more frequent than PUCR, and the 2 reflexes have distinctive characteristics in air and water stimuli. Both PRS and PUCR have implications for the evaluation of swallowing in infants. (J Pediatr 2007;151:597-603) wallowing activity in the fetus appears at around 11 weeks gestation,1 and sucking and swallowing skills develop progressively during fetal and neonatal maturation.2,3 The survival rate in preterm neonates is continually increasing, and one reason for prolonged hospitalization is the high prevalence of swallowing difficulty.4 Previous studies in infants and children have addressed the preparatory and oral phases of swallowing,1,5,6 the pharyngeal phase of swallowing, and the relationships with sleep and breathing7-9 and upper esophageal sphincter (UES) motor function.10-12 The integrated relationship among swallowing phases has not yet been systematiFrom the Sections of Neonatology, Pedically investigated in neonates. In a previous study, using manometric methods, we atric Gastroenterology, and Nutrition, Columbus Children’s Hospital and Decharacterized the UES contractile and relaxation properties during spontaneous swallowpartment of Pediatrics, Ohio State Uniinduced primary peristalsis sequences across the age spectrum from healthy premature versity College of Medicine and Public 13 infants to adult volunteers. Nonetheless, UES responses induced on pharyngeal stimHealth, Columbus, OH (S.J.); Section of Neonatology, Columbus Children’s Hosulation have not yet been described in neonates. pital, Columbus, OH (A.G., E.S.); Center The pharynx is the site of constant stimulation during breathing, bolus oral feeding, for Biostatistics, Ohio State University College of Medicine and Public Health and gastroesophageal reflux (GER) events. The neonatal aerodigestive tract is a common and Columbus Children’s Research Instisite of manipulation, both acute (as in apparent life-threatening events) and chronic (as in tute, Columbus, OH (S.F.), and Division of Gastroenterology and Hepatology, Departassisted respiration or assisted enteral nutrition). ment of Internal Medicine, and Dysphagia Consequently, the rationale for the present investigation was to evaluate the imInstitute, Medical College of Wisconsin, Milmediate responses resulting from pharyngeal stimulation in the population receiving waukee, WI (R.S.). Supported in part by National Institutes of neonatal intensive care. Our primary objectives were to define the frequency of occurrence Health grant RO1 DK 068158 (to S.J.). and elucidate the characteristics of pharyngeal–UES reflex interactions elicited on phaSubmitted for publication Aug 22, 2006; ryngeal provocation to oral feeding in prematurely born healthy human neonates. We last revision received Apr 5, 2007; accepted Apr 19, 2007. tested the hypothesis that pharyngeal stimulation with air and water infusions produce Reprint requests: Sudarshan R. Jadcherla, distinct neuromotor responses.
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EMG GA GEE GER PMA
Electromyography Gestational age Generalized estimating equation Gastroesophageal reflux Postmenstrual age
PRS PUCR UES
Pharyngeal reflexive swallowing Pharyngo– upper esophageal sphinctercontractile reflex Upper esophageal sphincter
MD, FRCPI, DCH, Section of Neonatology, Columbus Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.04.042
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METHODS Subjects Eligible subjects were orally feeding healthy, prematurely born neonates with appropriate growth at birth and at the time of study enrollment. The neonates’ gestational age (GA) was determined by maternal history and obstetric data. Postmenstrual age (PMA) was calculated by adding chronological age to GA. All subjects were examined by the principal investigator (SRJ) as well as by the attending neonatologist and were deemed healthy at study entry. None of the subjects had a presumed or proven clinical diagnosis of GER, and none received prokinetic agents during the study or at discharge. Neonates with congenital birth defects, neurologic abnormalities, perinatal asphyxia, gastrointestinal abnormalities, or recognizable chromosomal disorders were excluded from the study. All subjects had normal head ultrasound evaluation and were of appropriate growth for age at birth and at testing. The subjects had received respiratory assistance as needed due to premature birth. No subject had a respiratory, cardiac, or neurologic disease diagnosis at the time of evaluation. The study protocol was approved by the institutional review board of the Columbus Children’s Research Institute, and Health Insurance Portability and Accountability Act of 1996 (HIPAA) guidelines were followed. Informed consent was obtained from the parents of all subjects. Vital signs, including heart rate, respiratory rate, and oxygen saturation measured by pulse oximetry, were monitored to ensure patient safety. Pneumohydraulic Micromanometry The subjects underwent pharyngoesophageal manometry using a specially designed manometry catheter (Dentsleeve, Ontario, Canada) able to record motility from the pharyngeal port, the UES sleeve, and 3 esophageal ports. The pharyngeal infusion port was located 0.5 cm above the pharyngeal recording port. The catheter assembly was attached to a pneumohydraulic continuous micromanometric water perfusion system adapted for neonates, as described previously.14-16 Water was perfused at a rate of 0.02 mL/minute for each esophageal port, 0.04 mL/minute for the UES sleeve, and 0.01 mL/minute for the pharyngeal recording ports using the Dentsleeve perfusion pump. The response rate was 220 mm Hg/second for manometric ports and 850 mm Hg/second for the UES sleeve. These adjustments in perfusion rates were intended to maintain the patency of perfusion ports as well as sleeve performance, in addition to minimizing water load. Pressure transducers (DTX Plus TNF-R; Becton Dickinson, Franklin Lakes, NJ), and amplifiers (UPS 2020; Medical Measurement Systems, Dover, NH) were used to record the pressure signals. Concurrently, submental electromyography (EMG) was also synchronized with manometric signals to confirm the pharyngeal phase of swallow. EMG was measured using the UPS 2020 amplifier (Medical Measurement 598
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Systems); the input impedance was 2M2 Ohm differential. The output was the averaged signal representing the swallow.
Manometry Technique This technique has been described in detail in previous work.13-16 In brief, the manometric channels were calibrated at the level of the mid-axillary line. The catheter was placed transnasally in unsedated supine infants with the head in the midline. Positioning of the pharyngeal and UES channels was determined by the station pull-through technique in 0.5-cm intervals, such that the UES sleeve straddled the high-pressure zone at final placement. The subject was allowed to adapt for about 30 minutes before the pharyngeal infusion protocol was initiated. Pharyngeal Infusion Protocol Because the neonatal pharynx is a site of frequent stimulation with air and liquids, both air and sterile water were tested. First, graded volumes of air (0.1, 0.3, 0.5, 1.0, and 2.0 mL) were infused during a period of pharyngoesophageal quiescence to determine the threshold volume and dose– response relationship. Each volume was given in the same order, with a 40- to 60-second interval between infusions to ensure clearance and eliminate any residual effects. Similarly, graded volumes of sterile water (0.1, 0.3, and 0.5 mL) were infused. Each volume was given at least twice to evaluate consistency in responses. In pilot studies with water infusions, we noted consistent responses with 0.5 mL and absent responses with 0.01 mL; thus we did not test 1.0 mL for safety reasons and 0.01 mL due to lack of response. To evaluate the response by chance alone, we recorded sham infusion (0.0 mL)-related responses by placing an event marker under identical testing conditions. To minimize variability, the same investigator (SRJ) administered all infusions. A Priori Definitions and Data Analysis Pharyngeal reflexive swallow (PRS) is defined as pharyngeal swallow occurring within 5 seconds of pharyngeal infusion (Figure 1). PRS is identified based on the presence of a pharyngeal waveform along with a submental EMG signal, relaxation of the UES, and propagation of the waveform into the esophageal body. Pharyngo-UES-contractile reflex (PUCR) is defined as an increase in UES pressure ⬎ 4 mm Hg within 5 seconds of pharyngeal infusion (Figure 1). Pharyngo-UES-esophageal manometry waveforms were evaluated with each stimulus and compared with baseline motor activity by one of 3 investigators (SRJ, AG, or ES). The agreement rate among the 3 investigators for a change in pharyngo-UES motor activity was 1.0. The presence of UES relaxation or contraction with stimulus was further considered in the analysis. The agreement rate between 2 observers (SRJ and AG) was computed for the frequency of PRS and PUCR; the agreement was 1.00 (⫾standard error 0.11; Cohen’s kappa) for PRS and 0.94 (⫾0.17 SE; Cohen’s kappa) for PUCR. The Journal of Pediatrics • December 2007
Figure 1. Examples of PRS and PUCR evoked on pharyngeal air (A) and water (B) infusions in a representative neonate. PRS is characterized by a pharyngeal waveform, a submental EMG signal, and UES relaxation. PUCR is characterized by an increase in UES pressure after infusion.
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The following sensory variables were analyzed: threshold volume, defined as the smallest infusion volume resulting in either response at least 50% of the time (mean threshold volume for each infusion medium was also calculated for each reflex), and response time, defined as the time to onset of the reflex response from the peak stimulus (see Figure 1A). Several motor characteristics were analyzed, including the frequency occurrence of PRS or PUCR based on the a priori definition, the percentage distribution of PRS or PUCR or lack of a response to each stimulus mode, and the stimulus volume-response relationship for PRS and PUCR. Resting UES pressure was measured as the mean of 5 readings taken at end-expiration before each infusion. The change in UES pressure was calculated as the difference between the resting UES pressure and the maximum pressure increase after infusion.
Statistical Analysis Descriptive data are given as mean ⫾ standard deviation. Nonparametric tests (signed-rank tests) were performed when averages per patient were used for the analyses. When all of the individual data were used, generalized estimating equation (GEE) models with logit link functions with repeated measurements were performed to study the effect of media (water or air) on the binary outcome variables while controlling for different infusion volumes. Linear mixedeffects models with repeated measures were used to study the effect of media on continuous outcome variables while controlling for different infusion volumes. Square root transformation was used when normality assumption was not met. A P value ⬍ .05 was considered significant. STATA version 9.0 (StataCorp, College Station, TX) and SAS version 9.1 (SAS Institute, Cary, NC) were used for statistical analysis.
RESULTS Subject Characteristics Ten (5 females and 5 males) orally feeding healthy neonates (30 ⫾ 5 weeks gestation) with appropriate growth were tested at 39 ⫾ 4 weeks PMA (weight, 2.6 ⫾ 1.2 kg). The median Apgar scores were 6 at 1 minute and 8 at 5 minutes. The subjects tolerated the study with no changes in cardiorespiratory measures (heart rate, respiratory rate, and oxygen saturation). At discharge, all subjects received full oral feeds. No pharyngo-UES-esophageal motor activity was noted within 10 seconds after sham stimulus, compared with the baseline before the sham stimulus. Distribution and Frequency of Responses to Stimuli A total of 161 infusions were given in 10 subjects, of which 155 (106 air, 49 water; 96.3%) could be analyzed. The cumulative response rate was 30% (32 of 106) with air infusion and 76% (37 of 49) with water infusion (air vs water, P ⫽ .033; GEE). Further analysis of PRS and PUCR as individual responses revealed that PRS was the most frequent response 600
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Figure 2. Frequency and distribution of PRS and PUCR with air and water infusions. The frequency of PRS was greater with water than with air stimuli (P ⬍ .05; GEE). The frequency of PUCR was similar with water and air stimuli. Within the same media, the frequency of PRS was greater than PUCR with air and water stimuli.
with both air and water. The frequency of PRS was also greater with water infusions versus air infusions (P ⫽ .045; GEE) (Figure 2). PRS responses were solitary at 0.1 mL of water infusion, and multiple PRS events were noted with volume increments (Figure 3). No statistically significant difference in PUCR response between water and air infusions was found (P ⫽ .136; GEE).
Threshold Volumes and Response Latency The threshold volumes to evoke either response were significantly different: 0.4 ⫾ 0.3 mL for air and 0.2 ⫾ 0.1 mL for water (signed-rank test; P ⫽ .002). Water was a reliable stimulus and yielded a consistent response with less variability. The response times to evoke PRS for air and water were not significantly different: 1.9 ⫾ 1.3 seconds for air and 1.5 ⫾ 1.0 seconds for water (P ⫽ .138). The response times to evoke PUCR were marginally different: 0.6 ⫾ 1.2 seconds for air and 3.0 ⫾ 1.7 seconds for water (P ⫽ .063; signed-rank test). Stimulus VolumeⴚResponse Relationship for PRS With Air and Water Infusions Figure 4 shows the stimulus volume–response relationship for PRS with air and water infusions. PRS recruitment frequency (%) was compared at identical doses of air and water (0.1, 0.3, and 0.5 mL). At a volume of 0.3 mL, water infusions resulted in a 3-fold increase in PRS (31 ⫾ 36 for air and 91 ⫾ 19 for water; P ⫽ .010; GEE). At a volume of 0.5 mL, water infusions produced a 6-fold increase in PRS compared with 0.1-mL infusions (17 ⫾ 20 for air and 100 ⫾ 0 for water). Water stimuli resulted in multiple swallows in a dosedependent manner (see Figure 3). The frequency of pharyngo-UES swallows per infusion was 2 ⫾ 1 at 0.1 mL, 7 ⫾ 5 at 0.3 mL, and 5 ⫾ 2 at 0.5 mL (P ⫽ .0011; GEE using a square root transformation). The Journal of Pediatrics • December 2007
Figure 3. Examples of spontaneous swallow (A), solitary PRS (B), and multiple swallow sequences (C, D). Each swallow is associated with a submental EMG signal and UES relaxation. Recordings from P-Eso, M-Eso, and D-Eso represent proximal, middle, and distal esophageal motility, respectively. In A and B, note the propagation of peristaltic waveforms with solitary swallows. In C and D, multiple succeeding swallows inhibit the propagation of previous swallow. Only the terminal pharyngeal swallow resulted in a fully propagated sequence.
Figure 4. Stimulus volume–PRS response relationship with air and water infusions. Note the progressive increase in swallow frequency with graded volume increments of water, but not with air (P ⫽ .045).
Stimulus–Response Relationship for PUCR With Air and Water Infusions In terms of the frequency of PUCR with graded volumes of air or water infusions, the comparisons within and between air and water were similar and not significant.
DISCUSSION This study has investigated the unique relationship between the pharynx and UES elicited on pharyngeal provocation in healthy neonates using novel micromanometry methods. The major findings are that (1) PRS is a primary response to air and water stimuli, (2) liquid is a reliable medium for evoking PRS, (3) the occurrence and distribution of PRS are significantly greater with stimulus from incremen-
tal volumes of water than from incremental volumes of air, (4) the occurrence and distribution of PUCR are inconsistent with both air and water stimulus, (5) the recruitment rates of reflexes in air and water stimulus differ at identical volumes, (6) multiple deglutition sequences are present with incremental volumes of water, and (7) our approach provides a novel, safe, and reliable method to investigate sensorimotor aspects of neonatal swallow physiology. The aerodigestive protective mechanisms in human adult and animal models in response to pharyngeal infusions have been characterized previously.17-21 During the propagation of deglutition sequences, the airway is protected from anterograde aspiration by the pharyngeal, UES, and glottal reflexes.18,22,23 In adult studies, PUCR was the most frequent response, associated with closure of laryngeal vestibule. Such mechanisms may protect the airway from inadvertent entry of material into the larynx, as in GER events. The differences in voluntary, instructional, spontaneous, and reflexive swallowing have been characterized in adults at the aerodigestive tract and brain level,23 but have not been well described in neonates. Neonates’ feeding skills advance during development.3,13 Although sucking-swallowing characteristics have been described in neonates,3,5,6 methods to evaluate the pharyngeal and UES phases of swallowing are lacking. In this report, we define the sensory motor aspects of pharyngeal– UES interactions in healthy neonates as a prelude to applications in neonates at risk for dysphagia. Air stimuli resulted in inconsistent responses, possibly related to adaptation of the pharyngeal airway to constant
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movement of airflow with respiration, rather than triggering swallowing with each breath. Alternatively, as air stimuli increased in intensity, the frequency of PRS decreased. This may be a defensive reflex mechanism to prevent aerophagia. The neonatal pharynx can be exposed to high airflow rates delivered with continuous positive airway pressure systems. Aerophagia and gastric distention are common clinical problems in neonates and have been associated with various events, including GER, belching, hiccups, feeding problems, and spontaneous bowel perforation.24,25 Therefore, the infrequent air swallowing at higher volumes observed in our study may be a mechanism to prevent aerophagia and related problems. Water stimuli produced solitary swallow sequences at lower volumes and multiple swallow sequences at higher volumes. This indicates that greater liquid volumes recruit more swallow sequences to facilitate complete pharyngeal clearance. This phenomenon is a potential protective reflex mechanism to prevent aspiration at higher pharyngeal liquid volumes. Furthermore, water stimuli were more sensitive and consistent in evoking responses at lesser volumes compared with air stimuli. Interestingly, the response times were similar in water and air, supporting similar afferent– efferent neuromotor pathways with both stimuli. Unlike in adults,17,18 in neonates PRS, not PUCR, was the principal dynamic defensive response. This difference may be explained by structural differences,26 including the smaller pharyngo-UES segment, absence of an oropharynx, and relatively more elevated and anteriorly located larynx in neonates. Alternatively, the higher frequency of PRS in neonates may be due to functional differences in pharyngo–UES interactions compared with adults.13,17-19 Neonates lack volitional swallowing and frequently have poor UES contractile tone, resulting in relaxation of the cricopharyngeus muscle. In contrast, in adults, there may be an increase in cholinergic tone secondary to vagal neural output, manifesting as an increase in resting UES pressure.13 Mechanoreceptor or osmoreceptor stimulation of the pharynx may stimulate the vagal-glossopharyngeal afferents, eventually activating the vagal nuclei and efferents.15,27-31 The exact nature of mechanoreceptor or osmoreceptor stimulation is not well understood during development. We have found that the effects of sensory stimulation culminate in UES relaxation (PRS) or UES contraction (PUCR). Our findings may provide insight into the physiological basis for the safe pharyngo-UES clearance mechanisms in healthy neonates. The deglutition sequence is an important primary mechanism of aerodigestive clearance in neonates and may be the reason for frequent swallowing and autoresuscitation.8,9 We noted an increased frequency of multiple swallows with a larger pharyngeal liquid bolus, with the succeeding swallow inhibiting the esophageal propagation of the previous swallow. These aerodigestive defensive reflex responses may occur due to the presence of pharyngeal stimulus (entry of refluxate into the pharynx or presence of 602
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a bolus with feeding) and may complement the peristaltic reflexes or UES contractile reflex evoked on esophageal provocation.15,29,30,32 This study has some potential translational implications. Our findings may be used during a flexible endoscopic evaluation of swallow procedure in an infant with swallowing problems. Smaller volumes of air infusions into the pharynx through the endoscope would trigger fewer swallows (PRS) for evaluation. Conversely, the endoscope potentially could be used to infuse graded water infusions to induce more swallows (PRS). The lack of these responses could indicate a defect in the evolving neurocircuitry responsible for normal swallowing in infants. These methods may aid in the cribside evaluation of swallow physiology in neonates. Our data can serve as a reference for future studies in this vulnerable population. Pacing of swallowing skills may be dependent on bolus volume presented to the pharynx, and modification of oral feeding strategies may be appropriate in slowing down the bolus flow.33 Characterization of pharyngeal-UES motor defects is a necessary step toward improving swallow skills in infants at risk for dysphagia.
REFERENCES 1. Bu’Lock F, Woolridge MW, Bairn JD. Development of coordination of sucking, swallowing, and breathing: ultrasound study of term and preterm infants. Dev Med Child Neurol 1990;32:669-78. 2. Miller JL, Sonies BC, Macedonia C. Emergence of oropharyngeal, laryngeal and swallowing activity in the developing fetal upper aerodigestive tract: an ultrasound evaluation. Early Hum Dev 2003;71:61-87. 3. Gewolb IH, Vice FL, Schweitzer-Kenney EL, Taciak VL, Bosma JF. Developmental patterns of rhythmic suck and swallow in preterm infants. Dev Med Child Neurol 2001;43:22-7. 4. Mercado-Deane MG, Burton EM, Harlow SA, Glover AS, Deane DA, Guill MF, et al. Swallowing dysfunction in infants less than 1 year of age. Pediatr Radiol 2001;31:423-8. 5. Lau C, Alagurusamy R, Schanler RJ, Smith EO, Shulman RJ. Characterization of the developmental stages of sucking in preterm infants during bottle feeding. Acta Paediatr 2000;89:846-52. 6. Lau C, Smith EO, Schanler RJ. Coordination of suck-swallow and swallow respiration in preterm infants. Acta Paediatr 2003;92:721-7. 7. Pickens DL, Schefft GL, Thach BT. Pharyngeal fluid clearance and aspiration preventive mechanisms in sleeping infants. J Appl Physiol 1989;66:1164-71. 8. Thach BT. Maturation and transformation of reflexes that protect the laryngeal airway from liquid aspiration from fetal to adult life. Am J Med 2001;111:69S-77S. 9. Page M, Jeffery HE. Airway protection in sleeping infants in response to pharyngeal fluid stimulation in the supine position. Pediatr Res 1998;44:691-8. 10. Omari T, Snel A, Barnett C, Davidson G, Haslam R, Dent J. Measurement of upper esophageal sphincter tone and relaxation during swallowing in premature infants. Am J Physiol 1999;277:G862-6. 11. Willing J, Davidson GP, Dent J, Cook I. Effect of gastro-esophageal reflux on upper esophageal sphincter motility in children. Gut 1993;34:904-10. 12. Jadcherla SR, Shaker R. Esophageal and UES motor function in babies. Am J Med 2001;111:64-8. 13. Jadcherla SR, Duong HQ, Hofmann C, Hoffmann R, Shaker R. Characteristics of upper esophageal sphincter and esophageal body during maturation in healthy human neonates compared with adults. Neurogastroenterol Motil 2005;17:663-70. 14. Jadcherla SR. Manometric evaluation of esophageal-protective reflexes in infants and children. Am J Med 2003;115:157-60. 15. Jadcherla SR, Duong HD, Jadcherla SR, Duong HQ, Hoffmann RG, Shaker R. Esophageal body and upper esophageal sphincter motor responses to esophageal provocation during maturation in preterm newborns. J Pediatr 2003;143:31-8. 16. Gupta A, Jadcherla SR. The relationship between somatic growth and in vivo esophageal segmental and sphincteric growth in human neonates. J Pediatr Gastroenterol Nutr 2006;43:35-41. 17. Shaker R, Hogan WJ. Reflex-mediated enhancement of airway protective mechanisms. Am J Med 2000;108:8-14.
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18. Shaker R, Ren J, Xie P, Lang IM, Bardan E, Sui Z. Characterization of the pharyngo-UES contractile reflex in humans. Am J Physiol 1997;273:G854-8. 19. Dua K, Bardan E, Ren J, Sui Z, Shaker R. Effect of chronic and acute cigarette smoking on the pharyngoglottal closure reflex. Gut 2002;51:771-5. 20. Lang IM, Shaker R. An overview of the upper esophageal sphincter. Curr Gastroenterol Rep 2000;2:185-90. 21. Lang IM, Shaker R. Anatomy and physiology of the upper esophageal sphincter. Am J Med 1997;103:50S-5S. 22. Kendall KA. Oropharyngeal swallowing variability. Laryngoscope 2002;112: 547-51. 23. Kahrilas PJ, Dodds WJ, Dent J, Logemann JA, Shaker R. UES function during deglutition. Gastroenterology 1988;96:52-62. 24. Wilson SL, Thach BT, Brouillette RT, Abu-Osba YK. Coordination of breathing and swallowing in human infants. J Appl Physiol: Respir Environ Exercise Physiol 1981;50:851-8. 25. Hwang JB, Choi WJ, Kim JS, Lee SY, Jung CH, Lee YH, et al. Clinical features of pathologic childhood aerophagia: early recognition and essential diagnostic criteria. J Pediatr Gastroenterol Nutr 2005;41:612-6.
26. Arvedson JC, Lefton-Greif MA. Pediatric Videofluoroscopic Swallow Studies: A Professional Manual With Caregiver Guidelines. San Antonio, TX: The Psychological Corporation; 1998. 27. Goyal RK, Padmanabhan R, Sang Q. Neural circuits in swallowing and abdominal vagal afferent-mediated lower esophageal sphincter relaxation. Am J Med 2001;111:95-105. 28. Broussard DL, Altschuler SM. Central integration of swallow and airway-protective reflexes. Am J Med 2000;108:62-7. 29. Sengupta JN, Kauvar D, Goyal RK. Characteristics of vagal esophageal tensionsensitive afferent fibers in the opossum. J Neurophysiol 1989;61:1001-10. 30. Longhi EH, Jordan PH. Necessity of a bolus for propagation of primary peristalsis in the canine esophagus. Am J Physiol 1971;220:609-12. 31. Lang IM, Medda BK, Shaker R. Mechanisms of reflexes induced by esophageal distention. Am J Physiol Gastrointest Liver Physiol 2001;281:G1246-63. 32. Jadcherla SR, Hoffmann RG, Shaker R. Effect of maturation on the magnitude of mechanosensitive and chemosensitive reflexes in the premature human esophagus. J Pediatr 2006;141:77-82. 33. Arvedson JC. Management of pediatric dysphagia. Otolaryngol Clin North Am 1998;31:453-76.
50 Years Ago in The Journal of Pediatrics PULMONARY
INTERSTITIAL EMPHYSEMA WITH AIR-BLOCK SYNDROME
Berman E, Kahn A. J Pediatr 1957;51:457-60
Air-leak syndrome, usually involving pneumothorax, pneumomediastinum, and/or pulmonary interstitial emphysema (PIE), is often seen in contemporary neonatal intensive care unit (NICU) care. Some of these infants with PIE are dramatically ill with what has been termed “air-block syndrome.” Air-block syndrome with PIE is thought to be caused by escaping gas through ruptures in the small ventilating units of the lung into the perivascular sheaths, causing potentially catastrophic changes in compliance and restriction of pulmonary blood flow. In 1957, Berman and Kahn published a case report in The Journal describing a term infant who had increasing respiratory failure with pneumomediastinum and probable PIE. This infant was aggressively and successfully treated by mediastinotomy and drainage. The authors gave this example of air-block syndrome and stated their opinion that this clinical event occurred more frequently than reported. This single case report from 1957 stands in contrast to scores of cases reported in multiple series following the wide application of neonatal intensive care from the 1970s on. Although the reminders of treatment options are useful, it is of great potential value to reemphasize preventative strategies, such as reducing induced volutrauma. Additional understanding gained since this report in 1957 has helped us recognize the key injurious role of volutrauma to the immature lung. Volutrauma causes a range of injuries, from PIE and air-block syndrome to more insidious inflammatory changes associated with long-term pulmonary dysplasia. These manifestations of volutrauma continue to be seen in the NICU milieu all too often. Increased applied research and intelligent bedside application of ventilatory strategies in the NICU has significant promise in improving outcomes of the most vulnerable infants. Such strategies as less invasive respiratory support measures, physiological-driven use of end-expiratory strategies, more sophisticated understanding of ventilatory volume variance generated by patient–machine interactions, and increasingly precise control of delivered tidal volume under all circumstances could dramatically affect pulmonary and developmental outcomes. H. Farouk Sadiq, MD William J. Keenan, MD Neonatal-Perinatal Medicine Saint Louis University St Louis, Missouri 10.1016/j.jpeds.2007.06.034
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Objective To test the hypothesis that the sensorimotor characteristics of the reflexes evoked on stimulation with air and water infusions differ by studying the effect of pharyngeal stimulation on pharyngeal– upper esophageal sphincter (UES) interactions in healthy neonates. Study design Pharyngo-UES-esophageal manometry was recorded in 10 neonates at 39 ⴞ 4 weeks postmenstrual age. Pharyngeal infusions (n ⴝ 155) of air (0.1 to 2.0 mL) and sterile water (0.1 to 0.5 mL) were given. Two types of reflexes were recognized: pharyngeal reflexive swallowing (PRS) and pharyngo-UES-contractile reflex (PUCR). Frequency occurrence, distribution of reflexes, threshold volume, response time, and stimulus–response relationship were evaluated. Results The reflex response rates were 30% for air and 76% for water (P < .001). PRS was more frequent than PUCR with air and water (P < .05), even though the stimulation thresholds and response latencies were similar. Graded volumes of water but not air resulted in an increased frequency of PRS (P < .01). Conclusions PRS is more frequent than PUCR, and the 2 reflexes have distinctive characteristics in air and water stimuli. Both PRS and PUCR have implications for the evaluation of swallowing in infants. (J Pediatr 2007;151:597-603) wallowing activity in the fetus appears at around 11 weeks gestation,1 and sucking and swallowing skills develop progressively during fetal and neonatal maturation.2,3 The survival rate in preterm neonates is continually increasing, and one reason for prolonged hospitalization is the high prevalence of swallowing difficulty.4 Previous studies in infants and children have addressed the preparatory and oral phases of swallowing,1,5,6 the pharyngeal phase of swallowing, and the relationships with sleep and breathing7-9 and upper esophageal sphincter (UES) motor function.10-12 The integrated relationship among swallowing phases has not yet been systematiFrom the Sections of Neonatology, Pedically investigated in neonates. In a previous study, using manometric methods, we atric Gastroenterology, and Nutrition, Columbus Children’s Hospital and Decharacterized the UES contractile and relaxation properties during spontaneous swallowpartment of Pediatrics, Ohio State Uniinduced primary peristalsis sequences across the age spectrum from healthy premature versity College of Medicine and Public 13 infants to adult volunteers. Nonetheless, UES responses induced on pharyngeal stimHealth, Columbus, OH (S.J.); Section of Neonatology, Columbus Children’s Hosulation have not yet been described in neonates. pital, Columbus, OH (A.G., E.S.); Center The pharynx is the site of constant stimulation during breathing, bolus oral feeding, for Biostatistics, Ohio State University College of Medicine and Public Health and gastroesophageal reflux (GER) events. The neonatal aerodigestive tract is a common and Columbus Children’s Research Instisite of manipulation, both acute (as in apparent life-threatening events) and chronic (as in tute, Columbus, OH (S.F.), and Division of Gastroenterology and Hepatology, Departassisted respiration or assisted enteral nutrition). ment of Internal Medicine, and Dysphagia Consequently, the rationale for the present investigation was to evaluate the imInstitute, Medical College of Wisconsin, Milmediate responses resulting from pharyngeal stimulation in the population receiving waukee, WI (R.S.). Supported in part by National Institutes of neonatal intensive care. Our primary objectives were to define the frequency of occurrence Health grant RO1 DK 068158 (to S.J.). and elucidate the characteristics of pharyngeal–UES reflex interactions elicited on phaSubmitted for publication Aug 22, 2006; ryngeal provocation to oral feeding in prematurely born healthy human neonates. We last revision received Apr 5, 2007; accepted Apr 19, 2007. tested the hypothesis that pharyngeal stimulation with air and water infusions produce Reprint requests: Sudarshan R. Jadcherla, distinct neuromotor responses.
S
EMG GA GEE GER PMA
Electromyography Gestational age Generalized estimating equation Gastroesophageal reflux Postmenstrual age
PRS PUCR UES
Pharyngeal reflexive swallowing Pharyngo– upper esophageal sphinctercontractile reflex Upper esophageal sphincter
MD, FRCPI, DCH, Section of Neonatology, Columbus Children’s Hospital, 700 Children’s Drive, Columbus, OH 43205. E-mail: [email protected]. 0022-3476/$ - see front matter Copyright © 2007 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2007.04.042
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METHODS Subjects Eligible subjects were orally feeding healthy, prematurely born neonates with appropriate growth at birth and at the time of study enrollment. The neonates’ gestational age (GA) was determined by maternal history and obstetric data. Postmenstrual age (PMA) was calculated by adding chronological age to GA. All subjects were examined by the principal investigator (SRJ) as well as by the attending neonatologist and were deemed healthy at study entry. None of the subjects had a presumed or proven clinical diagnosis of GER, and none received prokinetic agents during the study or at discharge. Neonates with congenital birth defects, neurologic abnormalities, perinatal asphyxia, gastrointestinal abnormalities, or recognizable chromosomal disorders were excluded from the study. All subjects had normal head ultrasound evaluation and were of appropriate growth for age at birth and at testing. The subjects had received respiratory assistance as needed due to premature birth. No subject had a respiratory, cardiac, or neurologic disease diagnosis at the time of evaluation. The study protocol was approved by the institutional review board of the Columbus Children’s Research Institute, and Health Insurance Portability and Accountability Act of 1996 (HIPAA) guidelines were followed. Informed consent was obtained from the parents of all subjects. Vital signs, including heart rate, respiratory rate, and oxygen saturation measured by pulse oximetry, were monitored to ensure patient safety. Pneumohydraulic Micromanometry The subjects underwent pharyngoesophageal manometry using a specially designed manometry catheter (Dentsleeve, Ontario, Canada) able to record motility from the pharyngeal port, the UES sleeve, and 3 esophageal ports. The pharyngeal infusion port was located 0.5 cm above the pharyngeal recording port. The catheter assembly was attached to a pneumohydraulic continuous micromanometric water perfusion system adapted for neonates, as described previously.14-16 Water was perfused at a rate of 0.02 mL/minute for each esophageal port, 0.04 mL/minute for the UES sleeve, and 0.01 mL/minute for the pharyngeal recording ports using the Dentsleeve perfusion pump. The response rate was 220 mm Hg/second for manometric ports and 850 mm Hg/second for the UES sleeve. These adjustments in perfusion rates were intended to maintain the patency of perfusion ports as well as sleeve performance, in addition to minimizing water load. Pressure transducers (DTX Plus TNF-R; Becton Dickinson, Franklin Lakes, NJ), and amplifiers (UPS 2020; Medical Measurement Systems, Dover, NH) were used to record the pressure signals. Concurrently, submental electromyography (EMG) was also synchronized with manometric signals to confirm the pharyngeal phase of swallow. EMG was measured using the UPS 2020 amplifier (Medical Measurement 598
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Systems); the input impedance was 2M2 Ohm differential. The output was the averaged signal representing the swallow.
Manometry Technique This technique has been described in detail in previous work.13-16 In brief, the manometric channels were calibrated at the level of the mid-axillary line. The catheter was placed transnasally in unsedated supine infants with the head in the midline. Positioning of the pharyngeal and UES channels was determined by the station pull-through technique in 0.5-cm intervals, such that the UES sleeve straddled the high-pressure zone at final placement. The subject was allowed to adapt for about 30 minutes before the pharyngeal infusion protocol was initiated. Pharyngeal Infusion Protocol Because the neonatal pharynx is a site of frequent stimulation with air and liquids, both air and sterile water were tested. First, graded volumes of air (0.1, 0.3, 0.5, 1.0, and 2.0 mL) were infused during a period of pharyngoesophageal quiescence to determine the threshold volume and dose– response relationship. Each volume was given in the same order, with a 40- to 60-second interval between infusions to ensure clearance and eliminate any residual effects. Similarly, graded volumes of sterile water (0.1, 0.3, and 0.5 mL) were infused. Each volume was given at least twice to evaluate consistency in responses. In pilot studies with water infusions, we noted consistent responses with 0.5 mL and absent responses with 0.01 mL; thus we did not test 1.0 mL for safety reasons and 0.01 mL due to lack of response. To evaluate the response by chance alone, we recorded sham infusion (0.0 mL)-related responses by placing an event marker under identical testing conditions. To minimize variability, the same investigator (SRJ) administered all infusions. A Priori Definitions and Data Analysis Pharyngeal reflexive swallow (PRS) is defined as pharyngeal swallow occurring within 5 seconds of pharyngeal infusion (Figure 1). PRS is identified based on the presence of a pharyngeal waveform along with a submental EMG signal, relaxation of the UES, and propagation of the waveform into the esophageal body. Pharyngo-UES-contractile reflex (PUCR) is defined as an increase in UES pressure ⬎ 4 mm Hg within 5 seconds of pharyngeal infusion (Figure 1). Pharyngo-UES-esophageal manometry waveforms were evaluated with each stimulus and compared with baseline motor activity by one of 3 investigators (SRJ, AG, or ES). The agreement rate among the 3 investigators for a change in pharyngo-UES motor activity was 1.0. The presence of UES relaxation or contraction with stimulus was further considered in the analysis. The agreement rate between 2 observers (SRJ and AG) was computed for the frequency of PRS and PUCR; the agreement was 1.00 (⫾standard error 0.11; Cohen’s kappa) for PRS and 0.94 (⫾0.17 SE; Cohen’s kappa) for PUCR. The Journal of Pediatrics • December 2007
Figure 1. Examples of PRS and PUCR evoked on pharyngeal air (A) and water (B) infusions in a representative neonate. PRS is characterized by a pharyngeal waveform, a submental EMG signal, and UES relaxation. PUCR is characterized by an increase in UES pressure after infusion.
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The following sensory variables were analyzed: threshold volume, defined as the smallest infusion volume resulting in either response at least 50% of the time (mean threshold volume for each infusion medium was also calculated for each reflex), and response time, defined as the time to onset of the reflex response from the peak stimulus (see Figure 1A). Several motor characteristics were analyzed, including the frequency occurrence of PRS or PUCR based on the a priori definition, the percentage distribution of PRS or PUCR or lack of a response to each stimulus mode, and the stimulus volume-response relationship for PRS and PUCR. Resting UES pressure was measured as the mean of 5 readings taken at end-expiration before each infusion. The change in UES pressure was calculated as the difference between the resting UES pressure and the maximum pressure increase after infusion.
Statistical Analysis Descriptive data are given as mean ⫾ standard deviation. Nonparametric tests (signed-rank tests) were performed when averages per patient were used for the analyses. When all of the individual data were used, generalized estimating equation (GEE) models with logit link functions with repeated measurements were performed to study the effect of media (water or air) on the binary outcome variables while controlling for different infusion volumes. Linear mixedeffects models with repeated measures were used to study the effect of media on continuous outcome variables while controlling for different infusion volumes. Square root transformation was used when normality assumption was not met. A P value ⬍ .05 was considered significant. STATA version 9.0 (StataCorp, College Station, TX) and SAS version 9.1 (SAS Institute, Cary, NC) were used for statistical analysis.
RESULTS Subject Characteristics Ten (5 females and 5 males) orally feeding healthy neonates (30 ⫾ 5 weeks gestation) with appropriate growth were tested at 39 ⫾ 4 weeks PMA (weight, 2.6 ⫾ 1.2 kg). The median Apgar scores were 6 at 1 minute and 8 at 5 minutes. The subjects tolerated the study with no changes in cardiorespiratory measures (heart rate, respiratory rate, and oxygen saturation). At discharge, all subjects received full oral feeds. No pharyngo-UES-esophageal motor activity was noted within 10 seconds after sham stimulus, compared with the baseline before the sham stimulus. Distribution and Frequency of Responses to Stimuli A total of 161 infusions were given in 10 subjects, of which 155 (106 air, 49 water; 96.3%) could be analyzed. The cumulative response rate was 30% (32 of 106) with air infusion and 76% (37 of 49) with water infusion (air vs water, P ⫽ .033; GEE). Further analysis of PRS and PUCR as individual responses revealed that PRS was the most frequent response 600
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Figure 2. Frequency and distribution of PRS and PUCR with air and water infusions. The frequency of PRS was greater with water than with air stimuli (P ⬍ .05; GEE). The frequency of PUCR was similar with water and air stimuli. Within the same media, the frequency of PRS was greater than PUCR with air and water stimuli.
with both air and water. The frequency of PRS was also greater with water infusions versus air infusions (P ⫽ .045; GEE) (Figure 2). PRS responses were solitary at 0.1 mL of water infusion, and multiple PRS events were noted with volume increments (Figure 3). No statistically significant difference in PUCR response between water and air infusions was found (P ⫽ .136; GEE).
Threshold Volumes and Response Latency The threshold volumes to evoke either response were significantly different: 0.4 ⫾ 0.3 mL for air and 0.2 ⫾ 0.1 mL for water (signed-rank test; P ⫽ .002). Water was a reliable stimulus and yielded a consistent response with less variability. The response times to evoke PRS for air and water were not significantly different: 1.9 ⫾ 1.3 seconds for air and 1.5 ⫾ 1.0 seconds for water (P ⫽ .138). The response times to evoke PUCR were marginally different: 0.6 ⫾ 1.2 seconds for air and 3.0 ⫾ 1.7 seconds for water (P ⫽ .063; signed-rank test). Stimulus VolumeⴚResponse Relationship for PRS With Air and Water Infusions Figure 4 shows the stimulus volume–response relationship for PRS with air and water infusions. PRS recruitment frequency (%) was compared at identical doses of air and water (0.1, 0.3, and 0.5 mL). At a volume of 0.3 mL, water infusions resulted in a 3-fold increase in PRS (31 ⫾ 36 for air and 91 ⫾ 19 for water; P ⫽ .010; GEE). At a volume of 0.5 mL, water infusions produced a 6-fold increase in PRS compared with 0.1-mL infusions (17 ⫾ 20 for air and 100 ⫾ 0 for water). Water stimuli resulted in multiple swallows in a dosedependent manner (see Figure 3). The frequency of pharyngo-UES swallows per infusion was 2 ⫾ 1 at 0.1 mL, 7 ⫾ 5 at 0.3 mL, and 5 ⫾ 2 at 0.5 mL (P ⫽ .0011; GEE using a square root transformation). The Journal of Pediatrics • December 2007
Figure 3. Examples of spontaneous swallow (A), solitary PRS (B), and multiple swallow sequences (C, D). Each swallow is associated with a submental EMG signal and UES relaxation. Recordings from P-Eso, M-Eso, and D-Eso represent proximal, middle, and distal esophageal motility, respectively. In A and B, note the propagation of peristaltic waveforms with solitary swallows. In C and D, multiple succeeding swallows inhibit the propagation of previous swallow. Only the terminal pharyngeal swallow resulted in a fully propagated sequence.
Figure 4. Stimulus volume–PRS response relationship with air and water infusions. Note the progressive increase in swallow frequency with graded volume increments of water, but not with air (P ⫽ .045).
Stimulus–Response Relationship for PUCR With Air and Water Infusions In terms of the frequency of PUCR with graded volumes of air or water infusions, the comparisons within and between air and water were similar and not significant.
DISCUSSION This study has investigated the unique relationship between the pharynx and UES elicited on pharyngeal provocation in healthy neonates using novel micromanometry methods. The major findings are that (1) PRS is a primary response to air and water stimuli, (2) liquid is a reliable medium for evoking PRS, (3) the occurrence and distribution of PRS are significantly greater with stimulus from incremen-
tal volumes of water than from incremental volumes of air, (4) the occurrence and distribution of PUCR are inconsistent with both air and water stimulus, (5) the recruitment rates of reflexes in air and water stimulus differ at identical volumes, (6) multiple deglutition sequences are present with incremental volumes of water, and (7) our approach provides a novel, safe, and reliable method to investigate sensorimotor aspects of neonatal swallow physiology. The aerodigestive protective mechanisms in human adult and animal models in response to pharyngeal infusions have been characterized previously.17-21 During the propagation of deglutition sequences, the airway is protected from anterograde aspiration by the pharyngeal, UES, and glottal reflexes.18,22,23 In adult studies, PUCR was the most frequent response, associated with closure of laryngeal vestibule. Such mechanisms may protect the airway from inadvertent entry of material into the larynx, as in GER events. The differences in voluntary, instructional, spontaneous, and reflexive swallowing have been characterized in adults at the aerodigestive tract and brain level,23 but have not been well described in neonates. Neonates’ feeding skills advance during development.3,13 Although sucking-swallowing characteristics have been described in neonates,3,5,6 methods to evaluate the pharyngeal and UES phases of swallowing are lacking. In this report, we define the sensory motor aspects of pharyngeal– UES interactions in healthy neonates as a prelude to applications in neonates at risk for dysphagia. Air stimuli resulted in inconsistent responses, possibly related to adaptation of the pharyngeal airway to constant
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movement of airflow with respiration, rather than triggering swallowing with each breath. Alternatively, as air stimuli increased in intensity, the frequency of PRS decreased. This may be a defensive reflex mechanism to prevent aerophagia. The neonatal pharynx can be exposed to high airflow rates delivered with continuous positive airway pressure systems. Aerophagia and gastric distention are common clinical problems in neonates and have been associated with various events, including GER, belching, hiccups, feeding problems, and spontaneous bowel perforation.24,25 Therefore, the infrequent air swallowing at higher volumes observed in our study may be a mechanism to prevent aerophagia and related problems. Water stimuli produced solitary swallow sequences at lower volumes and multiple swallow sequences at higher volumes. This indicates that greater liquid volumes recruit more swallow sequences to facilitate complete pharyngeal clearance. This phenomenon is a potential protective reflex mechanism to prevent aspiration at higher pharyngeal liquid volumes. Furthermore, water stimuli were more sensitive and consistent in evoking responses at lesser volumes compared with air stimuli. Interestingly, the response times were similar in water and air, supporting similar afferent– efferent neuromotor pathways with both stimuli. Unlike in adults,17,18 in neonates PRS, not PUCR, was the principal dynamic defensive response. This difference may be explained by structural differences,26 including the smaller pharyngo-UES segment, absence of an oropharynx, and relatively more elevated and anteriorly located larynx in neonates. Alternatively, the higher frequency of PRS in neonates may be due to functional differences in pharyngo–UES interactions compared with adults.13,17-19 Neonates lack volitional swallowing and frequently have poor UES contractile tone, resulting in relaxation of the cricopharyngeus muscle. In contrast, in adults, there may be an increase in cholinergic tone secondary to vagal neural output, manifesting as an increase in resting UES pressure.13 Mechanoreceptor or osmoreceptor stimulation of the pharynx may stimulate the vagal-glossopharyngeal afferents, eventually activating the vagal nuclei and efferents.15,27-31 The exact nature of mechanoreceptor or osmoreceptor stimulation is not well understood during development. We have found that the effects of sensory stimulation culminate in UES relaxation (PRS) or UES contraction (PUCR). Our findings may provide insight into the physiological basis for the safe pharyngo-UES clearance mechanisms in healthy neonates. The deglutition sequence is an important primary mechanism of aerodigestive clearance in neonates and may be the reason for frequent swallowing and autoresuscitation.8,9 We noted an increased frequency of multiple swallows with a larger pharyngeal liquid bolus, with the succeeding swallow inhibiting the esophageal propagation of the previous swallow. These aerodigestive defensive reflex responses may occur due to the presence of pharyngeal stimulus (entry of refluxate into the pharynx or presence of 602
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a bolus with feeding) and may complement the peristaltic reflexes or UES contractile reflex evoked on esophageal provocation.15,29,30,32 This study has some potential translational implications. Our findings may be used during a flexible endoscopic evaluation of swallow procedure in an infant with swallowing problems. Smaller volumes of air infusions into the pharynx through the endoscope would trigger fewer swallows (PRS) for evaluation. Conversely, the endoscope potentially could be used to infuse graded water infusions to induce more swallows (PRS). The lack of these responses could indicate a defect in the evolving neurocircuitry responsible for normal swallowing in infants. These methods may aid in the cribside evaluation of swallow physiology in neonates. Our data can serve as a reference for future studies in this vulnerable population. Pacing of swallowing skills may be dependent on bolus volume presented to the pharynx, and modification of oral feeding strategies may be appropriate in slowing down the bolus flow.33 Characterization of pharyngeal-UES motor defects is a necessary step toward improving swallow skills in infants at risk for dysphagia.
REFERENCES 1. Bu’Lock F, Woolridge MW, Bairn JD. Development of coordination of sucking, swallowing, and breathing: ultrasound study of term and preterm infants. Dev Med Child Neurol 1990;32:669-78. 2. Miller JL, Sonies BC, Macedonia C. Emergence of oropharyngeal, laryngeal and swallowing activity in the developing fetal upper aerodigestive tract: an ultrasound evaluation. Early Hum Dev 2003;71:61-87. 3. Gewolb IH, Vice FL, Schweitzer-Kenney EL, Taciak VL, Bosma JF. Developmental patterns of rhythmic suck and swallow in preterm infants. Dev Med Child Neurol 2001;43:22-7. 4. Mercado-Deane MG, Burton EM, Harlow SA, Glover AS, Deane DA, Guill MF, et al. Swallowing dysfunction in infants less than 1 year of age. Pediatr Radiol 2001;31:423-8. 5. Lau C, Alagurusamy R, Schanler RJ, Smith EO, Shulman RJ. Characterization of the developmental stages of sucking in preterm infants during bottle feeding. Acta Paediatr 2000;89:846-52. 6. Lau C, Smith EO, Schanler RJ. Coordination of suck-swallow and swallow respiration in preterm infants. Acta Paediatr 2003;92:721-7. 7. Pickens DL, Schefft GL, Thach BT. Pharyngeal fluid clearance and aspiration preventive mechanisms in sleeping infants. J Appl Physiol 1989;66:1164-71. 8. Thach BT. Maturation and transformation of reflexes that protect the laryngeal airway from liquid aspiration from fetal to adult life. Am J Med 2001;111:69S-77S. 9. Page M, Jeffery HE. Airway protection in sleeping infants in response to pharyngeal fluid stimulation in the supine position. Pediatr Res 1998;44:691-8. 10. Omari T, Snel A, Barnett C, Davidson G, Haslam R, Dent J. Measurement of upper esophageal sphincter tone and relaxation during swallowing in premature infants. Am J Physiol 1999;277:G862-6. 11. Willing J, Davidson GP, Dent J, Cook I. Effect of gastro-esophageal reflux on upper esophageal sphincter motility in children. Gut 1993;34:904-10. 12. Jadcherla SR, Shaker R. Esophageal and UES motor function in babies. Am J Med 2001;111:64-8. 13. Jadcherla SR, Duong HQ, Hofmann C, Hoffmann R, Shaker R. Characteristics of upper esophageal sphincter and esophageal body during maturation in healthy human neonates compared with adults. Neurogastroenterol Motil 2005;17:663-70. 14. Jadcherla SR. Manometric evaluation of esophageal-protective reflexes in infants and children. Am J Med 2003;115:157-60. 15. Jadcherla SR, Duong HD, Jadcherla SR, Duong HQ, Hoffmann RG, Shaker R. Esophageal body and upper esophageal sphincter motor responses to esophageal provocation during maturation in preterm newborns. J Pediatr 2003;143:31-8. 16. Gupta A, Jadcherla SR. The relationship between somatic growth and in vivo esophageal segmental and sphincteric growth in human neonates. J Pediatr Gastroenterol Nutr 2006;43:35-41. 17. Shaker R, Hogan WJ. Reflex-mediated enhancement of airway protective mechanisms. Am J Med 2000;108:8-14.
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18. Shaker R, Ren J, Xie P, Lang IM, Bardan E, Sui Z. Characterization of the pharyngo-UES contractile reflex in humans. Am J Physiol 1997;273:G854-8. 19. Dua K, Bardan E, Ren J, Sui Z, Shaker R. Effect of chronic and acute cigarette smoking on the pharyngoglottal closure reflex. Gut 2002;51:771-5. 20. Lang IM, Shaker R. An overview of the upper esophageal sphincter. Curr Gastroenterol Rep 2000;2:185-90. 21. Lang IM, Shaker R. Anatomy and physiology of the upper esophageal sphincter. Am J Med 1997;103:50S-5S. 22. Kendall KA. Oropharyngeal swallowing variability. Laryngoscope 2002;112: 547-51. 23. Kahrilas PJ, Dodds WJ, Dent J, Logemann JA, Shaker R. UES function during deglutition. Gastroenterology 1988;96:52-62. 24. Wilson SL, Thach BT, Brouillette RT, Abu-Osba YK. Coordination of breathing and swallowing in human infants. J Appl Physiol: Respir Environ Exercise Physiol 1981;50:851-8. 25. Hwang JB, Choi WJ, Kim JS, Lee SY, Jung CH, Lee YH, et al. Clinical features of pathologic childhood aerophagia: early recognition and essential diagnostic criteria. J Pediatr Gastroenterol Nutr 2005;41:612-6.
26. Arvedson JC, Lefton-Greif MA. Pediatric Videofluoroscopic Swallow Studies: A Professional Manual With Caregiver Guidelines. San Antonio, TX: The Psychological Corporation; 1998. 27. Goyal RK, Padmanabhan R, Sang Q. Neural circuits in swallowing and abdominal vagal afferent-mediated lower esophageal sphincter relaxation. Am J Med 2001;111:95-105. 28. Broussard DL, Altschuler SM. Central integration of swallow and airway-protective reflexes. Am J Med 2000;108:62-7. 29. Sengupta JN, Kauvar D, Goyal RK. Characteristics of vagal esophageal tensionsensitive afferent fibers in the opossum. J Neurophysiol 1989;61:1001-10. 30. Longhi EH, Jordan PH. Necessity of a bolus for propagation of primary peristalsis in the canine esophagus. Am J Physiol 1971;220:609-12. 31. Lang IM, Medda BK, Shaker R. Mechanisms of reflexes induced by esophageal distention. Am J Physiol Gastrointest Liver Physiol 2001;281:G1246-63. 32. Jadcherla SR, Hoffmann RG, Shaker R. Effect of maturation on the magnitude of mechanosensitive and chemosensitive reflexes in the premature human esophagus. J Pediatr 2006;141:77-82. 33. Arvedson JC. Management of pediatric dysphagia. Otolaryngol Clin North Am 1998;31:453-76.
50 Years Ago in The Journal of Pediatrics PULMONARY
INTERSTITIAL EMPHYSEMA WITH AIR-BLOCK SYNDROME
Berman E, Kahn A. J Pediatr 1957;51:457-60
Air-leak syndrome, usually involving pneumothorax, pneumomediastinum, and/or pulmonary interstitial emphysema (PIE), is often seen in contemporary neonatal intensive care unit (NICU) care. Some of these infants with PIE are dramatically ill with what has been termed “air-block syndrome.” Air-block syndrome with PIE is thought to be caused by escaping gas through ruptures in the small ventilating units of the lung into the perivascular sheaths, causing potentially catastrophic changes in compliance and restriction of pulmonary blood flow. In 1957, Berman and Kahn published a case report in The Journal describing a term infant who had increasing respiratory failure with pneumomediastinum and probable PIE. This infant was aggressively and successfully treated by mediastinotomy and drainage. The authors gave this example of air-block syndrome and stated their opinion that this clinical event occurred more frequently than reported. This single case report from 1957 stands in contrast to scores of cases reported in multiple series following the wide application of neonatal intensive care from the 1970s on. Although the reminders of treatment options are useful, it is of great potential value to reemphasize preventative strategies, such as reducing induced volutrauma. Additional understanding gained since this report in 1957 has helped us recognize the key injurious role of volutrauma to the immature lung. Volutrauma causes a range of injuries, from PIE and air-block syndrome to more insidious inflammatory changes associated with long-term pulmonary dysplasia. These manifestations of volutrauma continue to be seen in the NICU milieu all too often. Increased applied research and intelligent bedside application of ventilatory strategies in the NICU has significant promise in improving outcomes of the most vulnerable infants. Such strategies as less invasive respiratory support measures, physiological-driven use of end-expiratory strategies, more sophisticated understanding of ventilatory volume variance generated by patient–machine interactions, and increasingly precise control of delivered tidal volume under all circumstances could dramatically affect pulmonary and developmental outcomes. H. Farouk Sadiq, MD William J. Keenan, MD Neonatal-Perinatal Medicine Saint Louis University St Louis, Missouri 10.1016/j.jpeds.2007.06.034
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